Current FDA Article on Test Undecanoate

[kelkel]

http://www.fda.gov/downloads/Advisor.../UCM348092.pdf

[austinite]

Thanks, Kel. Printing...

[marcus300]

Wont download for me

Can anyone give me a run down whats happening?

[MR-FQ320]

145 pages of evidence and arguements for and against the use of Nebido

[marcus300]

still being blocked, cant download..

can anyone give me a quick run down?

[austinite]

It's 100 pages, lol. Here's the intro and conclusion...

Introduction


AVEED™ is a depot formulation of testosterone undecanoate (TU) indicated for long-term testosterone replacement therapy (TRT) in hypogonadal men. In adult males with conditions associated with a deficiency or absence of endogenous testosterone, intramuscular (IM) administration of 750 mg AVEED maintains eugonadal testosterone concentration (300-1000 ng/dL) for up to 10 weeks. Following baseline administration of 750 mg, a second 750 mg dose is given at 4 weeks followed by 750 mg every 10 weeks thereafter.


AVEED (750 mg TU/3 mL) is the same formulation as Nebido® (1000 mg TU/4 mL) which is approved in 94 countries (including the European Union). The treatment regimen approved in rest of world is 1000 mg TU given at 10- to 14-week intervals with an optional dose given 6 weeks after the first dose. Nebido has been approved for worldwide use for over 9 years, and since its launch in 2003 through November 24, 2011, more than 3.1 million doses of Nebido have been sold, providing extensive postmarketing safety experience. In addition, safety data from 18 clinical trials conducted in 3,556 subjects treated with TU is available.

Key benefits of AVEED are (1) extended dosing interval of 10 weeks, (2) efficacious with 94.0% of subjects achieving a Cavg within the eugonadal range, (3) no risk of transference (unlike class labeling for all topical TRTs), and (4) mean testosterone levels not exceeding supraphysiological concentrations (unlike short acting injectable TRTs).


In 2009, the Food and Drug Administration (FDA) issued a complete response letter stating AVEED could not be approved due to FDA’s concern regarding 2 types of immediate postinjection reactions. These reactions consisted of an acute coughing episode immediately after injection. The reaction is thought to be caused by oil from the injection entering the blood stream and reaching the lung. This event is known as pulmonary oil micro-embolism, or by the acronym “POME.” FDA was also concerned about immediate post injection reactions that included clinical features consistent with anaphylaxis.


Immediate post-injection reactions are reported with short-acting injectable TRTs. The labels for both testosterone enanthate and testosterone cypionate list anaphylactoid reactions on their package inserts among observed adverse reactions. There are 2 studies in the literature in which short-acting injectables were used that noted post-injection cough at rates between 1.5 in 100 and 1 in 1000.(1,2)


Endo provided a New Drug Application (NDA) resubmission which presented additional data from a review of the clinical and postmarketing databases to identify and characterize all cases of POME and anaphylaxis. In addition to Endo’s adjudication of potential POME and anaphylaxis cases, an adjudication of potential POME and anaphylaxis cases by 2 independent adjudicators has been submitted to the FDA. These reviews were conducted to better assess the true rate of these post-injection reactions.

This briefing book provides a summary of the effectiveness and general safety experience with AVEED in clinical development and the safety experience reported in postmarketing with TU. Additional sections provide detailed findings from an independent adjudication of POME and anaphylaxis. Based on the independent adjudication, the rate of POME in the clinical studies was 1.5 cases (95% CI, 0-3.2) per 10,000 injections,1 and the reporting rate of POME in the postmarketing database was 0.7 cases (95% CI, 0.6-0.8) per 10,000 doses sold. The rate of anaphylaxis in the clinical studies was 0 cases (95% CI, 0-10.4) per 10,000 patients,2 and the reporting rate of anaphylaxis in the postmarketing database was 0.4 cases (95% CI, 0.3-0.5) per 10,000 patients.




Conclusion
Hypogonadism is a condition that merits TRT. The Endocrine Society recommends replacement
therapy for symptomatic men with androgen deficiency. Testosterone replacement can induce
and maintain secondary sex characteristics, improve BMD, sexual function, sense of well-being,
and muscle mass and strength.(3)


The goal of TRT is to achieve testosterone concentrations in the eugonadal range
(300-1000 ng/dL) in order to treat the symptoms and prevent the complications of the deficiency.


All currently available forms of TRT have limitations and no one form is best for all men. The
most popular forms of TRT – gels – must be applied daily leading to poor persistence, result in
skin reactions, are associated with transference to women and children (for gels), and, in a
proportion of men, result in inadequate testosterone replacement despite dose adjustment. Short-
acting IM injections result in wide swings in blood testosterone levels after each injection and
the need for relatively frequent administration (every 2 to 4 weeks).


Regardless of limitation, most patients discontinue therapy within several months. Persistence on
therapy is important for clinicians to evaluate a response to treatment as well as for patients to
achieve therapeutic benefit. The extended dosing interval of AVEED may contribute to the
increased persistence observed and may make it be more favorable for patients to remain on
therapy.


AVEED offers men with hypogonadism a new TRT formulation that achieves normal
testosterone levels in most patients (94.0% of subjects in study IP157-001 Parts C and C2).
AVEED does not carry the risk of transference, which may endanger children and women who
inadvertently come into contact with men taking topical testosterone gel products. AVEED does
not exceed supraphysiological testosterone levels like the short acting injectables. It does not
require a surgical procedure like the pellets and does not result in gum irritation like the buccal
preparation.


Like any pharmaceutical product, AVEED has its own profile of adverse reactions. Some of
those reactions it shares in common with all TRTs but 2 are specifically related to the oily
injection medium and are shared with the short-acting TRTs. These are POME and anaphylaxis.
After review of an extensive safety database of 18 completed clinical studies conducted in
3,556 subjects treated with TU and over 3.1 million vials sold during a 9-year postmarketing
experience, the frequency of both of these reactions can be described as rare.




Based on independently adjudicated results from the clinical database, POME occurs at a rate of




1.5 (95% CI, 0-3.2) cases per 10,000 injections. Similarly, based on independently adjudicated
results from the clinical database, anaphylaxis occurs at a rate of 0 (95% CI, 0-10.4) cases per
10,000 patients treated. Endo has proposed a Risk Management Plan that makes prescribers and
patients aware of these events, controls the circumstances around the time and place that
injections are administered, and teaches prescribers how to respond should a reaction occur.
Based on the benefits and risks detailed in this briefing book, AVEED offers another option with
unique characteristics for the patient and physician to consider.


15-Mar-2013 Endo Pharmaceuticals Solutions Inc. Page 99



AVEED™ Briefing Document
Advisory Committee Meeting




Endo believes that AVEED has a favorable benefit/risk ratio for men with hypogonadism who
require TRT giving them an improved chance to stay on therapy. It offers unique benefits not
available with other approved testosterone products and the large clinical development database
and postmarketing experience around the world indicate that the identified serious risks are
infrequent. Endo is confident that the proposed risk management plan – the product labeling and
the REMS program, along with the additional risk management interventions (including a
30-minute in-office post-injection wait and a controlled distribution system) – will effectively
mitigate the immediate post-injection risks associated with AVEED – POME and anaphylaxis. In
conclusion, AVEED fulfills an unmet need in the United States.